A dual role for oncostatin M signaling in the differentiation and death of mammary epithelial cells in vivo.
Recent studies in breast cancer cell lines have shown that oncostatin M (OSM) not only inhibits proliferation but also promotes cell detachment and enhances cell motility. In this study, we have looked at the role of OSM signaling in nontransformed mouse mammary epithelial cells in vitro using the KIM-2 mammary epithelial cell line and in vivo using OSM receptor (OSMR)-deficient mice. OSM and its receptor were up-regulated approximately 2 d after the onset of postlactational mammary regression, in response to leukemia inhibitory factor (LIF)-induced signal transducer and activator of transcription-3 (STAT3). This resulted in sustained STAT3 activity, increased epithelial apoptosis, and enhanced clearance of epithelial structures during the remodeling phase of mammary involution. Concurrently, OSM signaling precipitated the dephosphorylation of STAT5 and repressed expression of the milk protein genes beta-casein and whey acidic protein (WAP). Similarly, during pregnancy, OSM signaling suppressed beta-casein and WAP gene expression. In vitro, OSM but not LIF persistently down-regulated phosphorylated (p)-STAT5, even in the continued presence of prolactin. OSM also promoted the expression of metalloproteinases MMP3, MMP12, and MMP14, which, in vitro, were responsible for OSM-specific apoptosis. Thus, the sequential activation of IL-6-related cytokines during mammary involution culminates in an OSM-dependent repression of epithelial-specific gene expression and the potentiation of epithelial cell extinction mediated, at least in part, by the reciprocal regulation of p-STAT5 and p-STAT3.
Tiffen
Paul G
PG
Department of Pathology, University of Cambridge, Cambridge, United Kingdom.
Omidvar
Nader
N
Marquez-Almuina
Nuria
N
Croston
Dawn
D
Watson
Christine J
CJ
Clarkson
Richard W E
RW
D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D016923:Cell Death / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics*; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000378:metabolism / Q000502:physiology*; D005260:Female; D005786:Gene Expression Regulation; D007774:Lactation / Q000235:genetics / Q000378:metabolism; D008321:Mammary Glands, Animal / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008892:Milk / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D053683:Oncostatin M / Q000378:metabolism / Q000502:physiology*; D053681:Oncostatin M Receptor beta Subunit / Q000235:genetics / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology
D053681:Oncostatin M Receptor beta Subunit; C508349:Osmr protein, mouse; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; C494080:Stat1 protein, mouse; C494087:Stat3 protein, mouse; D053683:Oncostatin M; D048052:Mitogen-Activated Protein Kinase 3